ORGANIC
LETTERS
2004
Vol. 6, No. 25
4755-4757
Palladium-Catalyzed Intramolecular
O-Arylation of Enolates: Application to
Benzo[b]furan Synthesis
Michael C. Willis,*,† Dawn Taylor,† and Adam T. Gillmore‡
Department of Chemistry, UniVersity of Bath, Bath BA2 7AY, U.K., and Chemical
Research and DeVelopment Department, Pfizer Global Research and DeVelopment,
Sandwich, Kent CT13 9NJ, U.K.
Received October 1, 2004
ABSTRACT
A catalyst generated from Pd2(dba)3 and the ligand DPEphos effects intramolecular C−O bond formation between enolates and aryl halides in
the conversion of 1-(2-haloaryl)ketones directly into the corresponding benzofurans. Both cyclic and acyclic ketones are efficient substrates.
Thio ketones can also be employed allowing the preparation of the corresponding benzothiophenes.
Palladium-catalyzed C-N and C-O arylation reactions have
had a significant impact upon organic synthesis and are now
reliable and well-used processes.1 Intramolecular variants of
these reactions, leading to the synthesis of a variety of
heterocyclic structures, have also received considerable
attention.1 More recently, the use of palladium catalysis to
mediate carbonyl R-arylation reactions (C-arylation) has been
developed as a useful synthetic procedure and methods for
the arylation of ketones,2 esters,3,4 amides,5 and malonates6
have all been reported. In this paper, we demonstrate that
palladium-catalyzed intramolecular O-arylation of enolates
is an efficient process and can be used to prepare a variety
of substituted benzofurans.7
The benzo[b]furan ring system features in many naturally
occurring and designed molecules responsible for a diverse
range of biological responses. Accordingly, there exists a
wide selection of methods for the synthesis of this important
structural motif,8 including many based on palladium ca-
talysis.9 Some of the most useful methods for benzo[b]furan
synthesis are based on the palladium-catalyzed cyclization
of appropriately substituted alkenyl10 or alkynyl phenols;11
† University of Bath.
‡ Pfizer Global Research.
(1) For recent reviews on Pd-catalyzed C-O and C-N bond fomation,
see: (a) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E. I., Ed.; Wiley: New York, 2002; Vol. 2, p
1051. (b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E. I., Ed.; Wiley: New York, 2002; Vol. 2, p
1097. (c) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(d) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron
2002, 58, 2041.
(2) (a) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473.
(3) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(4) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
8410.
(7) For an example of this type of cyclization in the context of a tandem
reaction, see: Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1999, 72, 2345.
(8) For reviews dealing with benzofuran synthesis, see: (a) Hou, X.-L.;
Yang, Z.; Wong, H. N. C. Prog. Heterocycl. Chem. 2002, 14, 139. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491. (c) Horton, D.
A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893. (d) Donnelly,
D. M. X.; Meegan, M. J. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds,; Pergamon Press: New York, 1984;
Vol. 4, p 657.
(9) Reviews: (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: Amsterdam, 2000. (b) Nakamura, I.; Yamamoto,
Y. Chem. ReV. 2004, 104, 2127.
(10) Reviews: (a) Hosokawa, T.; Murahashi, S.-I. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E. I., Ed.;
Wiley: New York, 2002; Vol. 2, p 2169. (b) Zeni, G.; Larock, R. C. Chem.
ReV. 2004, 104, 2285.
(5) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(6) Aramendia, M. A.: Borau, V.; Jime´nez, C.; Marinas, J. M.; Ruiz, J.
R.; Urbano, F. J. Tetrahedron Lett. 2002, 43, 2847.
10.1021/ol047993g CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/02/2004